As one of the most metabolically active tissues, the structural and functional integrity of the eye depends on a regular oxygen supply and nutrients from the blood [Suk-Yee et al. (2012) Oxidative Medicine and Cellular Longevity 2012:1-10]. In order to meet this high metabolic demand, the eye contains several structurally and functionally distinct vascular beds, which supply oxygen and nutrients to ocular components critical for the maintenance of vision [Kiel J. W. (2010) The Ocular Circulation. San Rafael (Calif.) Morgan & Claypool Life Sciences, Chapter 2, Anatomy]. These include the retinal and choroidal vasculatures, which supply the inner and outer portions of the retina, respectively, and the limbal vasculature located at the periphery of the cornea. Injuries and diseases that impair the normal structure and/or function of blood vessels in the eye, particularly those associated with ischemia and vascular complications such as neovascularization, blood vessel leakage, and blood vessel occlusion, are among the leading causes of visual impairment and blindness [Kaur et al. (2008) Clinical Ophthalmology 2(4):879-999]. Such injuries and disease often result in hypoxia and/or increased oxidative stress (e.g., increased levels of reactive oxygen species) within the eye, which can be particularly damaging to the retina and ocular nerve. Accordingly, in many ischemic and microvascular insufficiency disorders, vision loss is due to one or more of retinal damage, optic nerve damage, and vitreous hemorrhage (extravasation, or leakage, of blood and fluid into the areas in and around the vitreous humor of the eye).
For example, diabetic retinopathy is one of the most common diseases affecting the retinal vasculature, which can manifest in both type 1 diabetes or type 2 diabetes patients [Shin et al. (2014) J Opthalmic Vis Res. 9(3):362-373]. At first, diabetic retinopathy is generally asymptomatic or only results in mild vision problems. However, left untreated, diabetic retinopathy eventually can result in blindness. In the early stage of the disease, classified as non-proliferative retinopathy, microaneurysms develop in the retina's blood vessels. As the disease progresses, more blood vessels become damaged or blocked resulting in ischemia, which promotes growth of new blood vessels (neovascularization) in attempt to compensate for reduced oxygen and nutrient circulation. This stage of the disease is called proliferative retinopathy. New blood vessels form along the retina and the surface of the clear vitreous gel that fills the inside of the eye. These new blood vessels have thin, fragile walls which are prone to fluid leakage (whole blood and/or some constituents thereof) and rupture. Such leakage leads to blood and/or fluid pooling within the layers of the retina and in the vitreous humor, clouding vision. Also, blood and/or fluid can leak into the macula of the retina, the part of the eye responsible for sharp, straight-ahead vision. As the macula swells, the patient's central vision becomes distorted. This condition is referred to as macular edema and, left untreated, can result in macular degeneration in diabetic patients.
Ischemia and microvascular pathology are also associated with many other ocular disorders including, for example, macular degeneration (e.g., age-related macular degeneration, juvenile macular degeneration, wet macular degeneration, Stargardt's disease, and Best's disease), retinal vein occlusion (e.g., central retinal vein occlusion, hemi-retinal vein occlusion, branch retinal vein occlusion, and ischemic retinal vein occlusion), retinal artery occlusion (e.g., central retinal artery occlusion, hemi-retinal artery occlusion, branch retinal artery occlusion, and ischemic retinal artery occlusion), ischemic optic neuropathy [e.g., anterior ischemic optic neuropathy (arteritic and non-arteritic) and posterior ischemic optic neuropathy], macular telangiectasia (type I or type II), retinal ischemia (e.g., acute retinal ischemia or chronic retinal ischemia), ocular ischemic syndrome, retinal vasculitis, and retinopathy of prematurity.
Most available treatments for vascular disorders of the eye are directed at ameliorating vascular and nerve damage and include, for example, laser photocoagulation therapy, low dose radiation, and surgery (e.g., removal of neovascular membranes and vitrectomy). Unfortunately, many of these therapies have limited or short lasting effects. For example, neovascular membranes, which initially respond to laser therapy, have high recurrent rates and there also is risk of vision loss due to damage during laser treatment. Similarly, there is a high rate of recurrence of neovacuolization in patients receiving low dose radiation therapy. Surgical removal of neovascular membranes and vitrectomy can result in retinal detachment and are frequently associated with cataract development following treatment [Benson et al. (1988) Ophthalmic Surgery 19(20):826-824]. Recently, various VEGF antagonists have been approved for use in age-related macular degeneration and trials are ongoing for other ocular indications. However, VEGF antagonist therapy also has been associated with various adverse complications [Falavarjani et al. (2013) Eye 27:787-794].
Thus, there is high unmet need for effective therapies for treating ocular disorders, particularly those associated with ischemia and/or microvascular insufficiency. Accordingly, it is an object of the present disclosure to provide methods for improving vision in patients in need thereof and treating vascular disorders of the eye.